1. Field of the Invention
This invention relates to the purification of N-morpholinoalkyl dihydropyridines.
2. Description of the Prior Art
U.S. Pat. No. 4,258,042 describes and claims N-morpholinoalkyl dihydropyridines of the formula ##STR1## wherein Ar is heteroaryl, cycloalkyl having from 3 to 7 carbon atoms, naphthyl, indanyl, indenyl, tetrahydronaphthyl or a radical of formula ##STR2## wherein each of R.sub.5, R.sub.6 and R.sub.7 is independently H, alkyl, aryl, halo, lower alkoxy, nitro, alkylmercapto, cyano, carboxy, carbalkoxy, sulfamyl, trifluoromethyl, hydroxy, acyloxy, methanesulfonyl, or acylamino; and R.sub.5 and R.sub.6 when taken together form a methylenedioxy; Z is alkylene containing 1 to about 5 carbon atoms in the principal chain, and each R.sub.1 is independently hydrogen, alkyl, or alkoxyalkyl, with the proviso that only one R.sub.1 may be hydrogen; R.sub.2 is lower alkyl; R.sub.3 and R.sub.4 are independently hydrogen or lower alkyl. The total number of carbon atoms in each of the alkyl, acyl, and alkoxy groups can range up to about 10, and preferably contain up to 6 carbon atoms. The substituent "Z" contains up to about 5 carbons in the principal chain, i.e. the straight chain of carbons between the terminal valences, but can be branched in that methyl and ethyl substituents can be present on the principal chain. Thus, the alkylene chain Z can contain a total number of carbon atoms greater than 5, preferably no more than about 8.
Heteroaryl as employed herein refers to any heterocyclic structure in which at least one of O, S and N are present as the hetero atoms. These include thiophene, furan, pyridine, thiazole, pyrimidine, pyrrole, benzofuran, quinoline, benzothiophene and substituted heterocycles.
N-morpholinoalkyl dihydropyridines can be prepared, as stated in the patent, by art-recognized procedures from known starting materials. A particularly convenient preparative method utilizes the following: ##STR3##
The reaction can be carried out in a solvent in the presence of sodium hydride, or any alkali metal hydride or alkoxide as is commonly employed in condensation reactions. The reaction is effected in two steps, the first metallation with the alkali metal compound, and the second, condensation with the halide, "X", containing compound, which is usually chloride. The hydrides are convenient since the progress of the metallation reaction can be followed by observing the evolution of hydrogen gas. The metallation step is normally carried out at room temperature. The reaction mixture thereafter is heated at elevated temperature, e.g. at steam bath temperature at or about 100.degree. C. depending on the boiling point of the selected solvent, and the halide compound is then added, usually in controlled amounts in dropwise fashion and, after addition is completed, the reaction mixture is digested by heating at the elevated temperature.
The product is then obtained in the usual fashion, as by cooling to cause precipitation or evaporation of the solvent to obtain the product as a residue.
The compounds so obtained possess high antihypertensive activity and as such are of particular value as antihypertensive agents. However, it has been observed that the use of the above-described method of preparation results in the production of N-morpholinoalkyl dihydropyridines that contain a small and varying amount of the starting material. ##STR4## This residual impurity which at times may be 0.5% or more is undesirable in compounds designed for clinical applications where essential requirements such as proper dose, potency, high purity and absence of side effects must be strictly met. While residual amounts of the starting material could be further reduced via classical means of purification such as chromatography, multiple recrystallization and the like, such means are cumbersome, impractical and costly, on a large scale.
Accordingly, it is the principal object of the present invention to provide a method of purification for N-morpholinoalkyl dihydropyridines.
It is a further object of the present invention to provide a large scale method of purification for N-morpholinoalkyl dihydropyridines.
It is another object of the present invention to provide a large scale, simple and economical method of purification for N-morpholinoalkyl dihydropyridines.
It is still another object of the present invention to produce N-morpholinoalkyl dihydropyridines that are essentially free of the residual starting material.